Mechanism of Human Chorionic Gonadotrophinmediated Immunomodulation in Pregnancy

Amolak S Bansal; Shabana A Bora; Srdjan Saso; J Richard Smith; Mark R Johnson; Meen-Yau Thum


Expert Rev Clin Immunol. 2012;8(8):747-753. 

In This Article

Trophoblastic Angiogenesis & hCG

There is increasing evidence supporting the importance of hCG in the trophoblastic invasion of the decidualized endometrium.[3,8] As such, hCG has been reported to encourage the apoptosis of endometrial cells via the upregulation of Fas ligand mRNA and protein on the extravillous trophoblast.[9] Interestingly, in a two-way communication, hCG-treated endometrial cells induced apoptosis of T cells in coculture experiments,[9] thereby reducing anti-fetal maternal cellular immunity. However, recently Fluhr et al. confirmed the ability of IFN-γ and TNF-α to sensitize endometrial stromal cells to fas-mediated apoptosis.[10] Although hCG was unable to alter this process directly, this is not surprising as hCG would normally influence implantation via reduced T- and NK-cell secretion of these cytokines. hCG has also been shown to significantly reduce E-selectin-mediated adherence of HepG2 cells in a microtiter plate assay and using human umbilical vein endothelial cells.[11] This is clearly relevant to reducing the recruitment of activated immune cells to the fetal–maternal interface.

From the aforementioned points, it is likely that hCG is an important regulator of the depth of embryonic invasion and defective hCG function has been proposed to produce deficient placentation.[12] The resulting tissue ischemia has been suggested to increase the risk of preeclampsia[13] and, if severe, may result in miscarriage. In this regard, it is interesting that women with preeclampsia had reduced levels of circulating free VEGF,[14] and hCG has been shown to stimulate the release of VEGF by the secretory-phase endometrium.[15] At the same, VEGF also inhibited the secretion of macrophage colony stimulating factor I and the subsequent neutrophil recruitment.[15] It is likely that hCG-associated angiogenic activity involves adenylyl cyclase activation with a resultant increase in cAMP and subsequent activation of the PKA.[16] The latter then induces phosphorylation of specific intracellular target proteins.[17] Insufficient glycosylation has been proposed as an important variable in defective hCG-stimulated angiogenesis, particularly in regard to the vessel remodeling performed by the extravillous trophoblast. This is likely mediated by hCG-induced metalloproteinase-2 and -9 secretion, with a reduced production of tissue inhibitor of metalloproteinases-1, -2 and -3.[18]